This invention generally relates to the use of photodynamic therapy as a method to modulate the postintervention vascular injury healing response.
Photodynamic therapy (PDT) is a technique in which wavelength-specific, visible light is applied to activate otherwise relatively nontoxic photosensitizer dyes (PS) to generate cytotoxic free-radicals. These PDT-generated free-radical moieties are thought to exert cytotoxic effects by lipid peroxidation of cellular membranes and organelles. Although initially developed for cancer therapy, there are a considerable number of recent experimental studies that examined PDT-mediated inhibition of intimal hyperplasia (IH) which is regarded as one important obstacle to a satisfactory long-term patency after invasive vascular procedures. Intimal hyperplasia originates from an injury to the blood vessel wall, resulting in luminal encroachment from cellular proliferation and matrix deposition. The biologic effects of PDT are strictly limited to the proximity of the PS molecules when they are light-activated, because the half-life of the free-radicals ranges in the area of microseconds. Since the necessary components for PDT-mediated effects include oxygen, PS, and light; the appropriate dosimetry, which is multifactorial, may be important for effective treatment.
The development of procedures to treat arterial occlusive disease represents an important area in the field of surgery. Besides vascular surgery, novel interventional techniques have been developed including balloon angioplasty, stent depolyment and atherectomy. However, restenosis remains the major obstacle to satisfactory long term patency after therapeutic interventions for the treatment of vascular disease. All forms of reconstruction, whether interventional or surgical, cause a degree of injury to the vessel wall, which result in a injury healing response. Intimal hyperplasia (IH) is defined as the early post-interventional migration of smooth muscle cells (SMC) and myofibroblasts into the subintimal space of the vessel, and leads to cell proliferation and the production of excessive amounts of matrix protein. Recent studies have shown that, in addition to IH through its production of a physical mass, changes can occur in arterial wall geometry. Defined as arterial remodeling, these changes can also play an important role by altering the artery circumference due to fibrotic contraction or compensatory dilatation. This process of arterial remodeling and the degree of IH together, determine whether and to what extent an artery will develop restenosis. Although the molecular basis of vascular postinterventional renarrowing is not fully understood, the development of restenotic lesions has been shown to involve the production of specific matrix molecules such as procollagen type I and the large chondroitin proteoglycan versican. These molecules modulate cell function (migration, proliferation), the activity of growth factors, and local concentrations of lipids in the vascular wall. Cell-matrix interactions may also provide the basis for constrictive remodeling, which resembles a similar phenomenon in a nonvascular injury response.
Among numerous mechanical and pharmacological approaches, several have been investigated to inhibit the occurrence of restenosis. However, only intravascular stents and ionizing irradiation have been proven to clinically reduce this process, however, they have not been without their own shortcomings such as restenosis and thrombosis and do not provide an adequate solution to the problem.
Therefore, a need exists for the treatment of IH and/or restenosis which addresses the limitations known within the art.
The present invention is directed to methods for modulating, e.g., preventing, inhibiting or minimizing, restenosis in a subject after the subject has had an intervention to reopen an obstructed blood vessel. This is performed by administering a therapeutically effective amount of a photosensitizer to the treated, injured site and irradiating this treated injured site with a therapeutically effective amount of light energy, such that restenosis in the subject is modulated. In preferred embodiments, the photosensitizer is benzoporphyrin-derivative monoacid ring at a concentration of 25 xcexcg/ml and the energy is delivered by laser at about 690 nm with an energy value of about 100 J/cm2. In another preferred embodiment, the photosensitizer is methylene blue (MB) at a concentration of about 250 xcexcg/ml to about 300 xcexcg/ml and the energy is delivered by laser at about 660 nm with an energy value of about 100 J/cm2.
The present invention is also directed to methods for modulating, e.g., preventing, inhibiting or minimizing, intimal hyperplasia in a subject by administering a therapeutically effective amount of a photosensitizer to a therapeutically intervened site and irradiating the treated site with a therapeutically effective amount of light energy, such that intimal hyperplasia in the subject is modulated. Typically the subject is a mammal, e.g., a human, a mouse, a rat, a horse, a dog, or cat.